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Meta-Analysis
. 2012 Jul 11;2012(7):CD008941.
doi: 10.1002/14651858.CD008941.pub2.

Vascular-endothelial-growth-factor (VEGF) targeting therapies for endocrine refractory or resistant metastatic breast cancer

Anna Dorothea Wagner  1 , Christoph Thomssen, Johannes Haerting, Susanne Unverzagt
Affiliations
Meta-Analysis

Vascular-endothelial-growth-factor (VEGF) targeting therapies for endocrine refractory or resistant metastatic breast cancer

Anna Dorothea Wagner et al. Cochrane Database Syst Rev. .

Abstract

Background: Vascular-endothelial-growth-factor (VEGF) is a key mediator of angiogenesis. VEGF-targeting therapies have shown significant benefits and been successfully integrated in routine clinical practice for other types of cancer, such as metastatic colorectal cancer. By contrast, individual trial results in metastatic breast cancer (MBC) are highly variable and their value is controversial.

Objectives: To evaluate the benefits (in progression-free survival (PFS) and overall survival (OS)) and harms (toxicity) of VEGF-targeting therapies in patients with hormone-refractory or hormone-receptor negative metastatic breast cancer.

Search methods: Searches of CENTRAL, MEDLINE, EMBASE, the Cochrane Breast Cancer Group's Specialised Register, registers of ongoing trials and proceedings of conferences were conducted in January and September 2011, starting in 2000. Reference lists were scanned and members of the Cochrane Breast Cancer Group, experts and manufacturers of relevant drug were contacted to obtain further information. No language restrictions were applied.

Selection criteria: Randomised controlled trials (RCTs) to evaluate treatment benefit and non-randomised studies in the routine oncology practice setting to evaluate treatment harms.

Data collection and analysis: We performed data collection and analysis according to the published protocol. Individual patient data was sought but not provided. Therefore, the meta-analysis had to be based on published data. Summary statistics for the primary endpoint (PFS) were hazard ratios (HRs).

Main results: We identified seven RCTs, one register, and five ongoing trials from a total of 347 references. The published trials for VEGF-targeting drugs in MBC were limited to bevacizumab. Four trials, including a total of 2886 patients, were available for the comparison of first-line chemotherapy, with versus without bevacizumab. PFS (HR 0.67; 95% confidence interval (CI) 0.61 to 0.73) and response rate were significantly better for patients treated with bevacizumab, with moderate heterogeneity regarding the magnitude of the effect on PFS. For second-line chemotherapy, a smaller, but still significant benefit in terms of PFS could be demonstrated for patients treated with bevacizumab (HR 0.85; 95% CI 0.73 to 0.98), as well as a benefit in tumour response. However, OS did not differ significantly, neither in first- (HR 0.93; 95% CI 0.84 to 1.04), nor second-line therapy (HR 0.98; 95% CI 0.83 to 1.16). Quality of life (QoL) was evaluated in four trials but results were published for only two of these with no relevant impact. Subgroup analysis stated a significant greater benefit for patients with previous (taxane) chemotherapy and patients with hormone-receptor negative status. Regarding toxicity, data from RCTs and registry data were consistent and in line with the known toxicity profile of bevacizumab. While significantly higher rates of adverse events (AEs) grade III/IV (odds ratio (OR) 1.77; 95% CI 1.44 to 2.18) and serious adverse events (SAEs) (OR 1.41; 95% CI 1.13 to 1.75) were observed in patients treated with bevacizumab, rates of treatment-related deaths were lower in patients treated with bevacizumab (OR 0.60; 95% CI 0.36 to 0.99).

Authors' conclusions: The overall patient benefit from adding bevacizumab to first- and second-line chemotherapy in metastatic breast cancer can at best be considered as modest. It is dependent on the type of chemotherapy used and limited to a prolongation of PFS and response rates in both first- and second-line therapy, both surrogate parameters. In contrast, bevacizumab has no significant impact on the patient-related secondary outcomes of OS or QoL, which indicate a direct patient benefit. For this reason, the clinical value of bevacizumab for metastatic breast cancer remains controversial.

PubMed Disclaimer

Conflict of interest statement

Professor Christoph Thomssen has received speaker honoraria, participated on the Advisory Board and received research funding from Roche.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: reviewers judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentage of all included studies.
4
4
Forest plot of comparison: 1 First‐line chemotherapy with versus without bevacizumab, outcome: 1.1 Progression‐free survival.
5
5
Forest plot of comparison: 2 Second‐line chemotherapy with versus without bevacizumab, outcome: 2.1 Progression‐free survival.
6
6
Forest plot of comparison: 1 First‐line chemotherapy with versus without bevacizumab, outcome: 1.2 Overall survival.
1.1
1.1. Analysis
Comparison 1 First‐line chemotherapy with versus without bevacizumab, Outcome 1 Progression‐free survival.
1.2
1.2. Analysis
Comparison 1 First‐line chemotherapy with versus without bevacizumab, Outcome 2 Overall survival.
1.3
1.3. Analysis
Comparison 1 First‐line chemotherapy with versus without bevacizumab, Outcome 3 Response rate.
2.1
2.1. Analysis
Comparison 2 Second‐line chemotherapy with versus without bevacizumab, Outcome 1 Progression‐free survival.
2.2
2.2. Analysis
Comparison 2 Second‐line chemotherapy with versus without bevacizumab, Outcome 2 Overall survival.
2.3
2.3. Analysis
Comparison 2 Second‐line chemotherapy with versus without bevacizumab, Outcome 3 Response rate.
3.1
3.1. Analysis
Comparison 3 Adverse effects, Outcome 1 Treatment‐related deaths.
3.2
3.2. Analysis
Comparison 3 Adverse effects, Outcome 2 Permanent discontinuation    .
3.3
3.3. Analysis
Comparison 3 Adverse effects, Outcome 3 Patients with SAE.
3.4
3.4. Analysis
Comparison 3 Adverse effects, Outcome 4 Patients with AE (grade ≥ 3).
3.5
3.5. Analysis
Comparison 3 Adverse effects, Outcome 5 Hypertension (grade ≥ 3).
3.6
3.6. Analysis
Comparison 3 Adverse effects, Outcome 6 Arterial/venous thromboembolism (grade ≥ 3).
3.7
3.7. Analysis
Comparison 3 Adverse effects, Outcome 7 Venous thromboembolic event (grade ≥ 3).
3.8
3.8. Analysis
Comparison 3 Adverse effects, Outcome 8 Arterial thromboembolic event.
3.9
3.9. Analysis
Comparison 3 Adverse effects, Outcome 9 Pulmonary embolism (grade ≥ 3).
3.10
3.10. Analysis
Comparison 3 Adverse effects, Outcome 10 Proteinuria (grade ≥ 3).
3.11
3.11. Analysis
Comparison 3 Adverse effects, Outcome 11 Gastrointestinal perforation (grade ≥ 3).
3.12
3.12. Analysis
Comparison 3 Adverse effects, Outcome 12 Bleeding/haemorrhage (grade ≥ 3).
3.13
3.13. Analysis
Comparison 3 Adverse effects, Outcome 13 Wound‐healing complications (grade ≥ 3).
3.14
3.14. Analysis
Comparison 3 Adverse effects, Outcome 14 Congestive heart failure (grade ≥ 3).
3.15
3.15. Analysis
Comparison 3 Adverse effects, Outcome 15 Left ventricular systolic dysfunction (grade ≥ 2 or 3).
3.16
3.16. Analysis
Comparison 3 Adverse effects, Outcome 16 Cardiomyopathy (grade ≥ 3).
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD008941

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